scholarly journals The Concentration of Large Extracellular Vesicles Differentiates Early Septic Shock From Infection

2021 ◽  
Vol 8 ◽  
Author(s):  
Latthawan Monnamorn ◽  
Chutima Seree-aphinan ◽  
Piyatida Molika ◽  
Polathep Vichitkunakorn ◽  
Kovit Pattanapanyasat ◽  
...  
Keyword(s):  
Septic Shock ◽  
Endothelial Cells ◽  
Mortality Rate ◽  
Extracellular Vesicles ◽  
Diverse Group ◽  
Disease Course ◽  
Longitudinal Trend ◽  
Blood Specimens ◽  
The Given ◽  
Over Time

Septic shock represents a subset of sepsis with severe physiological aberrations and a higher mortality rate than sepsis alone. Currently, the laboratory tools which can be used to identify the state of septic shock are limited. In pre-clinical studies, extracellular vesicles (EVs), especially large EVs (lEVs), have been demonstrated a role as functional inflammatory mediators of sepsis. However, its longitudinal trend during the disease course has not been explored. In this study, the quantities and subtypes of plasma-derived lEVs were longitudinally compared between patients with septic shock (n = 21) and non-sepsis infection (n = 9), who presented within 48 h of their symptom onset. Blood specimens were collected for seven consecutive days after hospital admission. lEVs quantification and subtyping were performed using an imaging flow cytometer. The experiments revealed a higher lEVs concentration in septic shock patients than infected patients at the onset of the disease. In septic shock patients, lEVs concentration decreased over time as opposed to infected patients whose lEVs concentration is relatively static throughout the study period. The major contributors of lEVs in both septic shock and infected patients were of non-leukocyte origins; platelets, erythrocytes, and endothelial cells released approximately 40, 25, and 15% of lEVs, respectively. Among lEVs of leukocyte origins, neutrophils produced the highest number of EVs. Nevertheless, the proportion of each subtype of lEVs among the given amount of lEVs produced was similar between septic shock and infected patients. These findings raise the possibility of employing lEVs enumeration as a septic shock identifying tool, although larger studies with a more diverse group of participants are warranted to extrapolate the findings to a general population.

Quantifying the evolution of tumor architecture using serial circulating tumor DNA.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 600-600
Author(s):  
Jason Henry ◽  
Jonathan M. Loree ◽  
John H. Strickler ◽  
Kanwal Pratap Singh Raghav ◽  
Van K. Morris ◽  
...  
Keyword(s):  
Allele Frequency ◽  
Limit Of Detection ◽  
Circulating Tumor Dna ◽  
Tumor Evolution ◽  
Disease Course ◽  
Serial Sampling ◽  
Blood Specimens ◽  
Serial Samples ◽  
Tumor Dna ◽  
Over Time

600 Background: There is limited data regarding changes in the genomic landscape in individual patients over time as serial tissue biopsy has risk and is of uncertain clinical benefit. The advent of circulating tumor DNA (ctDNA) allows for safe and repeated molecular sampling with the potential to investigate evolution of tumor architecture over the disease course. Methods: From 5/15 to 12/17, 116 patients with metastatic CRC had between three to 12 blood specimens taken over the treatment course. Plasma was tested using targeted NGS assay (Guardant360, Guardant Health, 68 gene). To account for variations in the amount of ctDNA in serial samples, a window of evaluable allele frequency was established for each patient as the fold change between the max allele frequency (mAF) and limit of detection for serial samples with the lowest mAF. Mutations not falling within this window were excluded from analysis. Substantial treatment induced selective pressure (SP) was defined as a decrease in the mutant mAF of > 50% in patients with at least an initial mAF of 1%. Results: 116 patients with a total of 317 serial blood samples were evaluable after accounting for ctDNA variations over time. Specimens were collected a median of 12 months apart, with a median of three specimens per patient. Thirteen patients (11%) did not have any changes in mutations on serial sampling, however the remainder of patients gained an average of 1.1 mutations per time point (mut/tp), and lost 1.0 mut/tp. 31% of patients demonstrated evidence of substantial treatment-induced SP. These patients were more likely to demonstrate a change in clonal architecture of the tumor (46% greater rate than those without SP, P = 0.04), predominantly through gain of new clones. In contrast, clonal hematopoiesis alterations that may be induced by chemotherapy, such as JAK2V617F, were neither gained or lost. Conclusions: After correction for variations over time in the total amount of ctDNA in circulation, we identify numerous changes in tumor architecture with serial sampling. For the first time in colorectal cancer we demonstrate that when treatment-induced SP is applied the rate of tumor evolution is increased, demonstrating potential value of monitoring changes in tumor architecture over the disease course.

scholarly journals Extracellular vesicles from human airway basal cells respond to cigarette smoke extract and affect vascular endothelial cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ashish Saxena ◽  
Matthew S. Walters ◽  
Jae-Hung Shieh ◽  
Ling-Bo Shen ◽  
Kazunori Gomi ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Cigarette Smoke ◽  
Extracellular Vesicles ◽  
Basal Cell ◽  
Mapk Signaling ◽  
Cigarette Smoke Extract ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Basal Cells ◽  
Human Airway

AbstractThe human airway epithelium lining the bronchial tree contains basal cells that proliferate, differentiate, and communicate with other components of their microenvironment. One method that cells use for intercellular communication involves the secretion of exosomes and other extracellular vesicles (EVs). We isolated exosome-enriched EVs that were produced from an immortalized human airway basal cell line (BCi-NS1.1) and found that their secretion is increased by exposure to cigarette smoke extract, suggesting that this stress stimulates release of EVs which could affect signaling to other cells. We have previously shown that primary human airway basal cells secrete vascular endothelial growth factor A (VEGFA) which can activate MAPK signaling cascades in endothelial cells via VEGF receptor–2 (VEGFR2). Here, we show that exposure of endothelial cells to exosome-enriched airway basal cell EVs promotes the survival of these cells and that this effect also involves VEGFR2 activation and is, at least in part, mediated by VEGFA present in the EVs. These observations demonstrate that EVs are involved in the intercellular signaling between airway basal cells and the endothelium which we previously reported. The downstream signaling pathways involved may be distinct and specific to the EVs, however, as increased phosphorylation of Akt, STAT3, p44/42 MAPK, and p38 MAPK was not seen following exposure of endothelial cells to airway basal cell EVs.

scholarly journals Pneumomediastinum in COVID-19 disease: Outcomes and relation to the Macklin effect

2021 ◽  
pp. 021849232110100
Author(s):  
João Brito ◽  
Paulo Gregório ◽  
Alessandro Mariani ◽  
Paula D’ambrosio ◽  
Mauro Filho ◽  
...  
Keyword(s):  
Mortality Rate ◽  
Retrospective Studies ◽  
Underlying Mechanism ◽  
Hemodynamic Instability ◽  
Disease Course ◽  
Lung Involvement ◽  
Radiological Findings ◽  
Disease Outcomes ◽  
Macklin Effect ◽  
Benign Course

Aim Pneumomediastinum (PM) is associated with several etiologies and mechanisms. Although it has been described more than 100 years ago, the literature is limited to small retrospective studies. This study aimed to follow patients with coronavirus disease (COVID-19) that developed PM during hospitalization and describe their clinical and radiological evolution. Methods A prospective cohort was developed with patients with PM, excluding those with aerodigestive trauma, inside a hospital COVID-19 dedicated hospital. Clinical variables including onset of symptoms, hemodynamic instability, associated complications, the need of interventions, and disease course were all recorded. Also, radiological findings such as the presence of the Macklin effect, extension of lung involvement by COVID-19, and characteristics of the PM were analyzed. Results Twenty-one patients with non-traumatic PM were followed, resulting in an overall incidence of 0.5% during the study period. Seven (33%) patients had associated pneumothorax and malignant/tension PM was observed in three (14%) cases. The Macklin effect could be found in 11 patients (52%) and the majority of them had more than 50% of lung involvement due to COVID-19. The mortality rate was 49%; however, no deaths were directly related to the PM. Conclusions PM incidence is probably increased in the severe acute respiratory syndrome caused by COVID-19, especially in those with greater involvement of the lungs, and the Macklin effect may be an important underlying mechanism of this complication. Usually, PM has a benign course, but complications like tension/malignant PM may occur requiring prompt detection and intervention.

scholarly journals Ubiquinone Metabolism and Transcription HIF-1 Targets Pathway Are Toxicity Signature Pathways Present in Extracellular Vesicles of Paraquat-Exposed Human Brain Microvascular Endothelial Cells

2021 ◽  
Vol 22 (10) ◽  
pp. 5065
Author(s):  
Tatjana Vujić ◽  
Domitille Schvartz ◽  
Anton Iliuk ◽  
Jean-Charles Sanchez
Keyword(s):  
Endothelial Cells ◽  
Human Brain ◽  
Extracellular Vesicles ◽  
Physiological State ◽  
Microvascular Endothelial Cells ◽  
Brain Microvascular Endothelial Cells ◽  
Cell Of Origin ◽  
Functional Changes ◽  
Data Independent Acquisition ◽  
Microvascular Endothelial

Over the last decade, the knowledge in extracellular vesicles (EVs) biogenesis and modulation has increasingly grown. As their content reflects the physiological state of their donor cells, these “intercellular messengers” progressively became a potential source of biomarker reflecting the host cell state. However, little is known about EVs released from the human brain microvascular endothelial cells (HBMECs). The current study aimed to isolate and characterize EVs from HBMECs and to analyze their EVs proteome modulation after paraquat (PQ) stimulation, a widely used herbicide known for its neurotoxic effect. Size distribution, concentration and presence of well-known EV markers were assessed. Identification and quantification of PQ-exposed EV proteins was conducted by data-independent acquisition mass spectrometry (DIA-MS). Signature pathways of PQ-treated EVs were analyzed by gene ontology terms and pathway enrichment. Results highlighted that EVs exposed to PQ have modulated pathways, namely the ubiquinone metabolism and the transcription HIF-1 targets. These pathways may be potential molecular signatures of the PQ-induced toxicity carried by EVs that are reflecting their cell of origin by transporting with them irreversible functional changes.

scholarly journals Delivery of Therapeutic Agents to the Central Nervous System and the Promise of Extracellular Vesicles

Pharmaceutics ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 492
Author(s):  
Charlotte A. René ◽  
Robin J. Parks
Keyword(s):  
Central Nervous System ◽  
Endothelial Cells ◽  
Nervous System ◽  
Blood Brain Barrier ◽  
Extracellular Vesicles ◽  
Therapeutic Agents ◽  
Target Cells ◽  
Significant Barrier ◽  
The Central Nervous System ◽  
Delivery Vehicles

The central nervous system (CNS) is surrounded by the blood–brain barrier (BBB), a semipermeable border of endothelial cells that prevents pathogens, solutes and most molecules from non-selectively crossing into the CNS. Thus, the BBB acts to protect the CNS from potentially deleterious insults. Unfortunately, the BBB also frequently presents a significant barrier to therapies, impeding passage of drugs and biologicals to target cells within the CNS. This review provides an overview of different approaches to deliver therapeutics across the BBB, with an emphasis in extracellular vesicles as delivery vehicles to the CNS.

Hypercoagulability in Septic Shock Patients With Thrombocytopenia

2021 ◽  
pp. 088506662110241
Author(s):  
Sang-Min Kim ◽  
Sang-Il Kim ◽  
Gina Yu ◽  
June-Sung Kim ◽  
Seok In Hong ◽  
...  
Keyword(s):  
Emergency Department ◽  
Septic Shock ◽  
Multivariate Analysis ◽  
Platelet Count ◽  
Mortality Rate ◽  
Confidence Interval ◽  
Sofa Score ◽  
Odds Ratio ◽  
Fibrinogen Level ◽  
Limited Information

Background: Despite thrombocytopenia, patients with sepsis often experience hypercoagulability. However, limited information is available on the prevalence and effect of hypercoagulability in patients with sepsis-induced thrombocytopenia. Hence, we evaluated the prevalence of hypercoagulability and the association between hypercoagulability and clinical outcomes in septic shock patients with thrombocytopenia. Methods: Thromboelastography (TEG) was performed prospectively in 1294 patients with septic shock at the emergency department (ED) between January 2016 and December 2019. After excluding 405 patients who did not require resuscitation, refused enrollment, or developed septic shock after ED presentation, 889 patients were included. We defined thrombocytopenia as an admission platelet count lower than 150,000/µl according to SOFA score. We defined hypocoagulability and hypercoagulability as coagulation index (CI)< −3 and >3 on TEG, respectively. Results: Of the 889 septic shock patients (mean age 65.6 ± 12.7 years, 58.6% male), 473 (53.2%) had thrombocytopenia. Eighty-five (18.0%) patients showed hypercoagulable TEG and73 (15.4%) patients showed hypocoagulable TEG. The hypercoagulable TEG group had a significantly higher fibrinogen level and a lower 28-day mortality rate than the normal and hypocoagulable TEG groups (518 vs. 347 and 315 mg/dL; 7.1% vs. 21.1% and 36.8%, P < 0.01, respectively). In multivariate analysis, hypercoagulable TEG was associated with a decreased mortality rate (odds ratio: 0.395; 95% confidence interval, 0.162-0.965). Conclusions: In septic shock patients with thrombocytopenia, hypercoagulability was not uncommon. TEG can quickly distinguish the hypercoagulability and hypocoagulability states and serve as a valuable tool for evaluating the degree and risk in septic shock patients with thrombocytopenia.

scholarly journals MicroRNAs and Extracellular Vesicles as Distinctive Biomarkers of Precocious and Advanced Stages of Breast Cancer Brain Metastases Development

2021 ◽  
Vol 22 (10) ◽  
pp. 5214
Author(s):  
Inês Figueira ◽  
Joana Godinho-Pereira ◽  
Sofia Galego ◽  
Joana Maia ◽  
János Haskó ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Endothelial Cells ◽  
Brain Metastases ◽  
Extracellular Vesicles ◽  
Triple Negative ◽  
Survival Rates ◽  
Brain Parenchyma ◽  
Advanced Stages ◽  
Breast Cancer Brain Metastases

Triple negative breast cancer presents higher mortality and poorer survival rates than other breast cancer (BC) types, due to the proneness to brain metastases formation, which are usually diagnosed at advanced stages. Therefore, the discovery of BC brain metastases (BCBM) biomarkers appears pivotal for a timely intervention. With this work, we aimed to disclose microRNAs (miRNAs) and extracellular vesicles (EVs) in the circulation as biomarkers of BCBM formation. Using a BCBM animal model, we analyzed EVs in plasma by nanoparticle tracking analysis and ascertained their blood-brain barrier (BBB) origin by flow cytometry. We further evaluated circulating miRNAs by RT-qPCR and their brain expression by in situ hybridization. In parallel, a cellular model of BCBM formation, combining triple negative BC cells and BBB endothelial cells, was used to differentiate the origin of biomarkers. Established metastases were associated with an increased content of circulating EVs, particularly of BBB origin. Interestingly, deregulated miRNAs in the circulation were observed prior to BCBM detection, and their brain origin was suggested by matching alterations in brain parenchyma. In vitro studies indicated that miR-194-5p and miR-205-5p are expressed and released by BC cells, endothelial cells and during their interaction. These results highlight miRNAs and EVs as biomarkers of BCBM in early and advanced stages, respectively.

scholarly journals A clinical staging proposal of the disease course over time in non-severe patients with coronavirus disease 2019

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yiting Lin ◽  
Yiqun Wu ◽  
Ping Zhong ◽  
Bingbo Hou ◽  
Jielan Liu ◽  
...  
Keyword(s):  
Inflammatory Markers ◽  
Clinical Signs ◽  
Clinical Staging ◽  
Disease Course ◽  
Prodromal Phase ◽  
The Third ◽  
Convalescent Phase ◽  
Secondary Damage ◽  
Remission Phase ◽  
Over Time

AbstractInformation on the clinical staging of coronavirus disease 2019 (COVID-19) is still limited. This study aimed to propose a clinical staging proposal of the disease course in non-severe patients with COVID-19. In this retrospective study, 108 non-severe patients with COVID-19 were grouped according to the duration from symptoms onset to hospital admission: ≤ 1 week, > 1 to 2 weeks, > 2 to 3 weeks, > 3 to 5 weeks, respectively. The dynamic changes of clinical signs were profiled across the four groups. A clinical staging proposal of the disease course over time was proposed from the perspective of the interaction between the virus and host. The prodromal phase, characterized by pneumonia, significant lymphopenia, and slightly elevated inflammatory markers, occurred in the first week after symptoms onset. In the second week, all the hematological and inflammatory markers were at the peak or bottom. Meanwhile, progressive pneumonia as well as the secondary damage of other organs (e.g. cardiac damage, coagulopathy, etc.) was significant during this period, making the disease progress into the apparent manifestation phase. In the third week, the improvement of the majority of clinical signs accompanied by a relatively high degree of inflammatory response defined the remission phase. After 3 weeks, patients were in the convalescent phase, in which all the indicators were maintained at a relatively normal level. We concluded that the disease course over time in non-severe patients with COVID-19 could be divided into four phases: the prodromal phase (in the first week), the apparent manifestation phase (in the second week), the remission phase (in the third week), and the convalescent phase (after 3 weeks), respectively. In clinical practice, tailored therapies should be considered seriously in different stages of the disease course.

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